Linezolid is a synthetic antibiotic used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics. A member of the oxazolidinone class of drugs, linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). The main indications of linezolid are infections of the skin and soft tissues and pneumonia (particularly hospital-acquired pneumonia), although off-label use for a variety of other infections is becoming popular. Linezolid is marketed by Pfizer under the trade names Zyvox™ (in the United States, United Kingdom, Australia, and several other countries), Zyvoxid™ (in Europe), and Zyvoxam™ (in Canada and Mexico). The current sales for linezolid are over one billion US dollars per year and rising in part because of its indication for the treatment of many forms of MRSA. Linezolid is quite expensive, as a course of treatment can cost up to several thousand U.S. dollars. Much of the high cost of linezolid has been attributed to the expense of its manufacture. Therefore, the development of new, more economical processes for manufacturing linezolid and pharmaceutically acceptable salts thereof are needed.
Described herein are efficient processes for the preparation of linezolid and pharmaceutically acceptable salts thereof. In one embodiment, the processes described herein include the step of preparing the oxazolidinone present in linezolid and pharmaceutically acceptable salts thereof from an oxirane and an isocyanate.
In another alternative aspect, the processes include the step of preparing 3-fluoro-4-chloronitrobenzene from 4-chloronitrobenzene and fluorine. In another alternative aspect, the processes include the step of preparing 3-fluoro-4-(1-morpholino)nitrobenzene, or a salt thereof, from 3-fluoro-4-halonitrobenzene and morpholine. In another alternative aspect, the processes include the step of preparing 3-fluoro-4-(1-morpholino)aniline, or a salt thereof, from 3-fluoro-4-(1-morpholino)nitrobenzene and a reducing agent. In another alternative aspect, the processes include the step of preparing 3-fluoro-4-(1-morpholino)phenyl isocyanate from 3-fluoro-4-(1-morpholino)aniline and an acylating agent. In another alternative aspect, the processes include the step of preparing a compound of the formula
or a salt thereof from 3-fluoro-4-(1-morpholino)phenyl isocyanate and an oxirane of the formula
where RA is halo or a protected amino group; and RB is halo, amino, or a protected amino group. In another alternative aspect, the processes include the step of preparing a compound of the formula
or a salt thereof from
and CH3C(O)SH.
In another embodiment, described herein are process that proceed in high overall yield. In another embodiment, described herein are process that do not require any purifications using chromatography. In another embodiment, described herein are process where the products from each step are isolated as solids and/or crystalline solids. In another embodiment, described herein are process that proceed with high enantiomeric excess. It is to be understood that the processes described herein may be performed using and to produce racemic material, or optically active material of either absolute configuration. It is also to be understood that the processes described herein may be routinely adapted to prepare any of a wide variety of materials having a predetermined enanatiomeric excess or a predetermined range of enanatiomeric excess.